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Glomerular endothelial cell heterogeneity in Alport syndrome
- Source :
- Scientific Reports, Scientific Reports, Vol 10, Iss 1, Pp 1-18 (2020)
- Publication Year :
- 2020
- Publisher :
- Nature Publishing Group UK, 2020.
-
Abstract
- Glomerular endothelial cells (GEC) are a crucial component of the glomerular physiology and their damage contributes to the progression of chronic kidney diseases. How GEC affect the pathology of Alport syndrome (AS) however, is unclear. We characterized GEC from wild type (WT) and col4α5 knockout AS mice, a hereditary disorder characterized by progressive renal failure. We used endothelial-specific Tek-tdTomato reporter mice to isolate GEC by FACS and performed transcriptome analysis on them from WT and AS mice, followed by in vitro functional assays and confocal and intravital imaging studies. Biopsies from patients with chronic kidney disease, including AS were compared with our findings in mice. We identified two subpopulations of GEC (dimtdT and brighttdT) based on the fluorescence intensity of the TektdT signal. In AS mice, the brighttdT cell number increased and presented differential expression of endothelial markers compared to WT. RNA-seq analysis revealed differences in the immune and metabolic signaling pathways. In AS mice, dimtdT and brighttdT cells had different expression profiles of matrix-associated genes (Svep1, Itgβ6), metabolic activity (Apom, Pgc1α) and immune modulation (Apelin, Icam1) compared to WT mice. We confirmed a new pro-inflammatory role of Apelin in AS mice and in cultured human GEC. Gene modulations were identified comparable to the biopsies from patients with AS and focal segmental glomerulosclerosis, possibly indicating that the same mechanisms apply to humans. We report the presence of two GEC subpopulations that differ between AS and healthy mice or humans. This finding paves the way to a better understanding of the pathogenic role of GEC in AS progression and could lead to novel therapeutic targets.
- Subjects :
- 0301 basic medicine
Male
Pathology
Biopsy
Kidney Glomerulus
Glomerular diseases
Nephritis, Hereditary
Cell Separation
Transcriptome
Mice
0302 clinical medicine
Focal segmental glomerulosclerosis
Genes, Reporter
Chronic kidney disease
Multidisciplinary
Glomerulosclerosis, Focal Segmental
Flow Cytometry
Apelin
Proteinuria
APOM
Disease Progression
Medicine
medicine.symptom
Signal Transduction
Adult
medicine.medical_specialty
Adolescent
Transgene
Science
Inflammation
Mice, Transgenic
Biology
Article
03 medical and health sciences
Young Adult
medicine
Animals
Humans
Alport syndrome
Renal Insufficiency, Chronic
Gene Expression Profiling
Glomerulosclerosis
Endothelial Cells
medicine.disease
Mice, Inbred C57BL
030104 developmental biology
Microscopy, Fluorescence
Gene expression
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 20452322
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....8d4429b1c58f9623a738935f1cb062df